In the previous patent application PI 0501290-2, the state of the art with respect to vaccines against streptococci of the beta hemolytic group A type was duly described. This state of the art will be described again here, since this invention refers to the same subject.
As it is known in the art, rheumatic fever (RF) is a disease caused by infection by the group A beta hemolytic streptococcus, or S. pyogenes, a disease that is manifested in children between age 3 and 18, who present genetic susceptibility factors and who were not treated. The illness is initially manifested in the clinical form of polyarthritis (pains in the large articulations), followed by a clinical condition that involves two main manifestations: Sydenham's chorea and rheumatic carditis.
The chorea manifests in about 20-30% of patients with rheumatic fever (RF); the affected organ is the central nervous system (CNS) and the manifestations are translated into involuntary movements, psychiatric disorders, which disappear with adequate treatment.
Rheumatic carditis manifests in about 30-45% of patients with rheumatic fever (RF); it is characterized by an acute heart inflammation, initially in the myocardium, and produce serious, progressive and permanent lesions in the valve tissue, affecting mainly the mitral and aortic valves and triggering chronic rheumatic heart disease (RHD). The treatment of RHD in more advanced stages is surgical. Considering the age range of manifestation of the disease, children between age of 7 and 12, they frequently have to be operated for correction of valve lesions or to substitute the valves by biological prostheses (Snitcowski, 1996).
In Brazil, 90% of child cardiac surgeries result from rheumatic valve lesions. The cardiac surgeries in adult rheumatic individuals correspond to 30% of this total (Data from the Ministry of Health, DATA-SUS).
Epidemiology:
Rheumatic fever (RF) and chronic rheumatic heart disease (RHD) are still considered as a public health problem in developing and underdeveloped countries. It is estimated that there are more than 50 million cases of rheumatic fever (RF) in the world, and, according to recent data from the World Health Organization (WHO), there are records of 14 million cases of chronic rheumatic heart disease (RHD) in the world. The prevalence of RHD is higher than 10 children in each 1000 with RF in various countries, among them: Iran, Thailand, China, Bolivia, Pakistan, India, Australia, Argelia, Egypt and Morocco. Brazil has an average of 6.5 children with RHD per 1000 RF carriers. Moreover, more than 18 million cases of streptococci per year and more than 500000 deaths per year by streptococci are recorded at the WHO (2004).
Pathogenesis of the Disease:
Rheumatic fever (RF) is considered an autoimmune disease resulting from the defense immune response triggered against the group A beta hemolytic streptococcus, or S. pyogenes, and that, in some individuals (those with susceptibility to the illness), produces an aggressive response against the organism's own proteins through biological mimicry mechanisms.
It is currently known that antibodies and the immune response mediated by T-Cell lymphocytes are responsible for the cross reactions against proteins of the human tissue (heart, articulations, kidney, brain) (revised by Cunningham, 2000; Guilherme et al, 1995). These cross-reactions occur due to the similarity in the structure or residues of amino acids, especially with protein M of the streptococcus. 
The M-protein sequences were analyzed and published in the 1980s (Manjula e Philipis, 1984, and Miller et al, 1998), and permitted great advance in the knowledge of the regions capable of triggering the illness, through a number of scientific works published by several groups.
The M-protein contains regions of repetitions of amino acid residues, and is subdivided into an amino-terminal portion and a carboxy-terminal portion. In the amino-terminal portion are located the residues of amino acids that define the streptococcus serotype. The carboxy-terminal portion is quite conserved among the different serotypes and has groups of amino acids groups that repeat themselves more than once (Fischetti, 1991).
Several segments of the amino-terminal region are described because they are involved in the triggering of the disease (rheumatic fever and/or chronic rheumatic heart disease), especially through cross-reaction with proteins of the cardiac tissue (revised by Cunningham, 2000 and Guilherme et al, 2005).
It is interesting to note that until the 80s, it was believed that cross-reactions between the streptococcus and the proteins of the human tissue resulted only from an antibody-mediated immune response. From the description of the presence of inflammatory infiltrates in the cardiac tissue with predominance of CD4+ T lymphocyte (Raizada et al, 1983, and Kemeny et al, 1989), the Applicant demonstrated that the heart lesions were mediated by these cells (CD4+ T lymphocytes). This evidence was defined by the detection of the immune response of the cross reaction between proteins isolated from fragments of human cardiac tissue (myocardium and valvular), by infiltrating T lymphocytes of the heart lesion in patients that carried RHD, obtained through a surgical act, to correct the valve lesions (Guilherme et al, 1995). Subsequently, the Applicant described the presence of great number of mononuclear cells that produced particularly inflammatory cytokines (interferon gama, IFNg; and tumor necrosis factor alpha, TNFa) in the cardiac tissue (myocardium and mitral and/or aortic valves) of patients suffering from rheumatic heart disease. The relevant finding of this work was the observation of the presence of great number of cytokine producing cells, which regulate the inflammation (interleukines 10 and 4, IL-10 and IL-4) in the myocardium and rare cells producing the IL-4 regulatory cytokine, in the valve tissue. This finding showed why post-streptococcal myocarditis heals in approximately 4 weeks and the lesions of the mitral and/or aortic valves are slow, progressive and permanent (Guilherme et al, 2004).
Considering that rheumatic fever is an autoimmune disease, understanding the pathogenesis of rheumatic fever is fundamental to its prevention, because it leads to care being taken to produce a vaccine against the cause agent, the group A beta hemolytic streptococcus (S. pyogenes), in the sense of not triggering the autoimmune disease.
There already are several vaccines against group A beta hemolytic streptococcus. 
Prof. James B. Dale (University of Tennessee Research Foundation) is carrying out research to produce a vaccine based on the sequences of the amino-terminal residues of protein M, which confer the streptococcus specificity. He has several published works (Beachey et al, 1987; Dale et al, 1993; Dale et Chang, 1995; Dale et al, 1999, a, b and c); and he has already analyzed the response capacity in 26 different serotype animal models. There are several patents filed in his behalf, among which U.S. Pat. No. 6,716,433, filed on Sep. 10, 1998 and granted on Apr. 6, 2004 (“GROUP A STREPTOCOCCAL VACCINES”).
Recently, the group published a “phase I” work, using vaccine formulation containing 06 different serotypes in the form of a recombinant protein containing N-terminal segments of the 06 serotypes. Cross-reaction control was conducted on human tissue slices and only the humoral response (antibody mediated) was evaluated (Kotloff, 2004). The multivalent vaccine produced to prevent streptococcal infection against 26 serotypes of S. pyogenes, is undergoing phase II clinical tests (McNeil et al, 2005).
Prof. Vincent Fischetti (The Rockefeller University) is conducting research for the production of a vaccine based on the sequences of the carboxy-terminal residues of protein M, which confer streptococcus specificity. By cloning the gene that codifies protein M6 (portions N and C-terminal) the group found that 56 different streptococci serotypes presented the homology of the amino acids sequence in the carboxy-terminal region (Scott et al, 1985 e 1986). Through intranasal inoculation of peptides of the carboxy-terminal region of protein M6 in rabbits, Prof. Fischetti's group showed the possibility of altering the group A streptococcus bacterial colonization (Bessen et Fischetti, 1988, a and b). Using vaccines with synthetic peptides with shared sequences covalently linked and conjugated with the sub-unit of the CTB cholera toxin, they induced the formation of IgA type antibodies specific for protein M with a protective activity in the serum and in the saliva of mice (Bessen et Fischetti, 1990, and Fluckiger et al, 1998).
In subsequent works, these authors used the vaccinia virus as a vector, containing the total sequence of the C-terminal portion of protein M6, to produce the recombinant vaccine—VV: M6-, showing that a single intranasal dose was capable of preventing the heterologous streptococci bacterial colonization. Intradermal immunization was ineffective (Fischetti et al, 1985). The high cost of conjugation and the intranasal use of the vaccinia virus, in the models cited above limited the use of these models as a safe, effectively and financially accessible vaccine. Tests with commensal bacteria as vectors were also used (Fischetti et al, 1993; Medaglini et al, 1995). The use of this commensal vector as a vehicle of the vaccine is under analysis. Preliminary results have suggested that the vector was safe and well tolerated, when administered orally or nasally, in 150 healthy voluntaries (Kotloff et al, 2005).
There are some patents filed in his name, among them, U.S. Pat. No. 6,602,507, filed on Jan. 6, 1995 and granted on Jan. 5, 2003 (“SYNTHETIC PEPTIDES FROM STREPTOCOCCAL M PROTEIN AND VACCINES PREPARED THEREFROM”). The formulation of vaccine of the C-terminal portion expresses how fusion protein on the surface of Streptococcus gordoni, is currently undergoing clinical phase I tests (WHO, 2006).
Prof. M. Good has been approaching the use of peptides from the C-terminal portion as a possible vaccine model in Australia, where the incidence of streprotococcal infections in the aborigine populations, and consequently of rheumatic fever is high. Australian researchers identified a peptide composed by 09 amino acid residues of the C-terminal portion, capable of producing opsonizing antibodies in immunized mice. This antibody was also present in the serum of normal individuals and patients with rheumatic disease (Pruksakorn et al, 1994, and Brandt et al, 1997). Recently, the group has been working with a combination of segments from the amino-terminal portions of some serotypes prevailing in Australia and the segment of the carboxy-terminal portion, referred to as J14 (Dunn et al, 2002; Olive et al, 2002). The group's most recent results show that segment J14 (29 amino acid residues) favor the development of protective antibodies, capable of inducing fagocytosis in an experimental model of mouse, against various strains of S. pyogenes from isolated points from the endemic regions of Australia. The in vivo challenge of these animals confirmed the protective capacity of peptide J14 in several formulations (Vohra et al, 2005; Batzloff et al, 2005; Olive et al, 2005).